Bicyclic ferrocenes



P Patented 3 417 118 dried 1,2-dimethoxyethane with stirring for about 20 minutes at 20-25 C. The reaction mixture is diluted with BICYCLIC FERROCENES Richard A. Schnettler, Milwaukee, and John T. Suh and Watef with f g B'u'ferro' Claude I. Judd, Mequon, Wis., assignors to Colgateceny ).acry w 16 IS 150 ate m t e ethereal P Palmolive Company, New York, NY, a corporation 5 tract, 1 s then hydrogenated under standard hydrogenatlon f Delaware conditions in the presence of an 85% platinum oxide cata- N Drawing. Filed Sept. 26, 1966, Ser. No. 581,735 lyst, and the reaction mixture filtered to yield ethyl [El-(1- 6 Claims. (Cl. 260-439) ferrocenyl) propionate. The propionate is heated with ethanolic sodium hydroxide at 80 C. for about one hour, the mixture cooled, diluted and acidified with glacial acetic acid to precipitate fl-ferrocenylpropionic acid. The acid This application relates to novel ferrocene derivatives, processes of preparing them and uses for such compounds. 0 Ferrocene is the commonly accepted name for dicyclopentadienyliron or bi ey lo ent di ylim is first'treated with trifiuoroacetic anhydride in anhydrous The novel compounds of the present invention may be dichloromethane at 0 C., and then treated with 10% represented by the following formulae: sodium hydroxide solution to yield an a-keto-1,1-tri- I -(CH -(CH Fe Fe Z 2) Z) R wherein R is hydrogen, an alkyl having 1 to 8 carbon methylene ferrocene. [Rinehart and Curby, JACS 79, atoms as methyl, ethyl, isopropyl, butyl, hexyl and an 3290 (1957)].

aryl, particularly phenyl or a nuclear substituted phenyl The u-keto-1,1'-trimethylene ferrocene may then be such as a chlorophenyl, or an aralkyl, particularly a treated with a mixture of N-methyl-N'-nitro-N-nitrosophenyl-lower alkyl such as benzyl, phenethyl, phenylisoquanidine and an alkali hydroxide, such as potassium hypropyl and diphenylmethyl; X is hydrogen, bromo or droxide, in ether to form the corresponding fi-keto-l,l'-

chloro, n is 0 or 1; and Y and Z are preferably hydrogen, tetramethyleneferrocene. The penta and hexa derivatives but may also be halogen such as chloro or bromo, trimay be formed ina similar manner. fluoromethyl or lower alkyl. The process may be illustrated as follows:

Cl'lzNZ I e Fe The compounds of the present invention may be conin which Y and Z are as previously described and repre- VelllelltlY P p from a B' -L '-P Y y sent groups which do not interfere with or partake in the ferrocene of the formula reactions.

The B-keto-l,1-methyleneferrocenes are the basic starty ing material for the preparation of both the compounds 2 of Formula 1 and those of Formula 2. For example, the compounds of Formula 1 in which n is 0 are conveniently Fe prepared by treating the B-keto-l,1'-tetramethylene ferrocone with methyltriphenylphosphonium bromide and (CI-I butyl lithium under nitrogen to form the corresponding l3 methylene 1,1 tetramethyleneferrocene. The thus formed ii-methylene derivative may then be treated with an ethyl trihaloacetate such as ethyl trichloroacetate in the presence of a suitable catalyst, such as sodium methoxide, to form the corresponding spiro[2,2-dichlorocycloin which all symbols are as previously described.

The ketones employed as starting materials may be conveniently prepared by adding ferrocene portionwise to a mixture of N-methyl formanilide and phosphorus oxy- 1 P ,l y which p chloride. The mixture is treated with sodium acetate and treatment with lithium aluminum hydride yields the correstirred, and the resulting mixture extracted with ether, sponding SpirO[cyC10propane-l,fi- (l,1"-tetramethyleneand the formylferrocene isolated from the ether extract. ferrocene)]. The thus obtained ketone can be then treated The formylferrocene is then treated with a dispersion of in the manner described to form the compouds of For- 50% sodium hydride and triethylphosphonoacetate in mula 1.

The process may be illustrated as follows:

in which Y and Z are as previously described and represent groups which do not interfere with or partake in the reaction.

Representative of the compounds which may be prepared by the described process are the following: ,B-methylenel 1"-tetramethyleneferrocene,

Spir0[2,2 dichlorocyclopropane 1,,8 (1,1" tetramethyleneferrocene) Spir0[cyclopropane 1, 8 (1',1" tetramethyleneferrocene)],

Spir0[2,2 dichlorocyclopropane 1,13 (1,1" pentarnethyleneferrocene) Spiro[cyclopropane 1,;3 (1',1" pentamethyleneferrocene)],

Spir0[2,2 dibromocyclopropane LB (1',1" hexamethyleneferrocene) and (cir MARIA Spir0[cyclopropane 1,;3 (1,1" hexamethyleneferrocene)].

The compounds of Formula 2 are conveniently prepared by treating an appropriate ketone with a Grignard reagent to form fl-hydroxy derivative, then treating that compound with potassium bisulfate at an elevated temperature (e.g. 130) to form the corresponding exocyclic olefin and the ABq-B-methyl derivative. The latter compound .is then treated with an ethyl trihaloacetate, such as ethyl trichloroacetate, to form the corresponding [3, dihalomethylene derivative and that compound treated with lithium aluminum hydride to form the [SE -methylene derivative.

The process may be illustrated as follows:

Y GI Fe QDX (CH (CH in which X and Y are groups which do not interfere with or partake in the reactions.

Representative of the compounds which may be prepared by the above process are the following: Afi,-y-fi-methyl-1,l'-tetramethyleneferrocene,

1 ,7 dichloromethylene p methyl 1,1 tetramethyleneferrocene,

1 ,7 methylene ,8 methyl 1,1 tetramethyleneferrocene,

fin dibromomethylene ,8 phenyl 1,1 pentamethyleneferrocene,

13, methylene 8 phenyl 1,1 pentamethyleneferrocene,

1 ,7 methylene p butyl 1,1 tetramethyleneferrocene,

1 ,7 methylene ,3 phenyl 1,1 tetramethyleneferrocene, and

fin methylene p benzyl 1,1 tetramethyleneferrocene.

While for purposes of illustration the preparation of relatively simple compounds has been described, it will be readily apparent to those skilled in the art that dilferent and more complex substituents than those described for R, X and Y may be attached to the molecules by conventional techniques.

The ferrocene derivatives of the present invention show promise as highly stable organo-iron sources for use in a variety of chemical procedures, e.g., polymerization reactions and the like. In addition, they can be used as petroleum additives such as anti-knock agents or combined with pharmaceutical diluents and formed into suitable oral or parenteral dosage forms such as capsules, tablets or solutions, and employed as hematinics for the treatment of iron deficiencies in animals. Such pharmaceutical dosage forms will generally contain approximately to 500 mg. of the novel compounds.

The following examples illustrate the preparation of the novel compounds:

Example 1.-A 3,'y-,6-methyl-1,1'-tetrarnethyleneferrocene and B methylene-1,1'-tetramethyleneferrocene (1:1 mixture) A mixture of 2.44 g. (0.00904 mole) S-hydroxy-fimethyl-l,1-tetramethyleneferrocene and 5.0 g. potassium bisulfate is heated at 160 for 1 /2 hours. The mixture is cooled, dissolved in benzene and chromatographed on silica gel. Elution with benzene gives 2.1 g. (91%) of Afi -fl-methyl-l,1-tetramethyleneferrocene and B-methylene-1,l-tetramethyleneferrocene in the form of yellow crystals, M.P. 53-55 Analysis-Calm. for C H Fe: C, 71.45; H, 6.40; Fe, 22.20. Found: C, 71.67; H, 6.43; Fe, 22.21.

Example 2./3-methylene-l,1'-tetramethyleneferrocene To 100 ml. dry ether is added 7.0 g. (0.02 mole) methyltriphenylphosphonium bromide and 2.55 g. (0.016 mole) butyl lithium under nitrogen. When the mixture turns deep orange, 1.0 g. (0.004 mole) 1,1-tetramethyleneferrocene is added as a dry powder. The mixture is stirred under nitrogen at room temperature for 2 hours, diluted with 100 ml. water, washed with water, dried and the solvent removed to give a gold oil. This was chromatographed over silica gel (petroleum ether) and 0.75 g. (75%) of fl-methylene-1,1-tetramethyleneferrocene in the form of a yellow solid is obtained, M.P. 66-69.

Analysis.Calcd. for C H Fe: C, 71.45; H, 6.40. Found: C, 70.94; H, 6.29.

Example 3.--fi,'y-dichloromethylene-[i-methyl-1,1'-

tetramethyleneferrocene To 200 ml. cyclohexane, 5.8 g. (0.107 mole) sodium methoxide and 2.7 g. (0.0107 mole) AB,' -;3-methyl-1,1'- tetramethyleneferrocene and fl-methylene-l,1'-tetramethyleneferrocene' (1:1 mixture) cooled to 0 C. is added 20.5 g. (0.107 mole) ethyl trichloroacetate. The mixture is stirred for six hours at 0 C., water (100 ml.) added and stirred with the mixture for 30 minutes, after which the organic layer is separated from the aqueous and washed with water and dried. Removal of solvent gives a yellow oil which is chromatographed over 200 g. silica gel. Eluting with petroleum ether and taking 50 ml. fractions effects separation. Fractions 1-12 are combined and crystallized from ethanol to give 0.750 g. (21%) offiyydichloromethylene-fl-methyl 1,1 tetramethyleneferrocene in the form of yellow crystals, M.P. 152-154".

Analysis.-Calcd. for C H Cl Fe: C, 57.36; H, 4.81; Cl, 21.16; Fe, 16.67. Found: C, 57.02; H, 4.75; Cl, 21.36; Fe, 16.67.

Example 4.Spiro[2,2-dichlorocyclopropane-1,,B-(1,1- tetramethyleneferrocene) Fractions 1518 of Example 3 are combined and crystallized from ethanol to give 0.790 g. (22%) of a spiro[2, Z-dichlorocyclopropane 1,5 (1,1 tetramethyleneferrocene)] in the form of yellow crystals, M.P. -96".

Analysis.Calcd. for C H Cl Fe: C, 57.36; H, 4.81; CI, 21.16; Fe, 16.67. Found: C, 56.91; H, 4.72; Cl, 21.54; Fe, 16.72.

Example 5 .}8,'y-methylene-fi-methyl-1, 1 tetramethyleneferrocene To 3.4 g. (0.09 mole) LAH in ml. tetrahydrofuran (freshly distilled from LAH) is slowly added 1.2 g. (0.0037 mole) ,8,y-dich1oromethylene-;3-methyl-l,1- tetramethyleneferrocene dissolved in 70 ml. tetrahydrofuran. The mixture is stirred and refluxed for 43 hours after which it is cooled and a mixture of tetrahydrofuran: EtOAc (1:1) is added to destroy the excess LAH. The mixture is diluted with brine (200 ml.), extracted with EtOAc and dried. Removal of solvent gives a yellow solid which is recrystallized from methanol to give 0.69 g. (70% j8,'y-methylene-p-methyl-1,1-tetramethyleneferrocene in the form of yellow crystals, M.P. l29130.

Analysis.Calcd. for C H Fe: C, H, 6.82. Found: C, 72.60; H, 6.72.

Example 6.Spiro [cyclopropane-1,B( 1,1- tetramethyleneferrocene) To 100 ml. freshly distilled tetrahydrofuran and 3.0 g. (0.08 mole) LAH is added 1.17 g. (0.0035 mole) spiro[2, 2 dichlorocyclopropane-1,5-(1',1"-tetramethyleneferrocene)] in 70 ml. tetrahydrofuran dropwise at room temperature over a period of 15 minutes. The mixture is then stirred and refluxed for 20 hours. At the end of this time the system is cooled and a mixture of tetrahydrofuran: EtOAc 1:1) is slowly added to decompose the excess LAH. Water (200 ml.) is added and the mixture poured into 300 ml. brine, extracted with ethyl acetate, Washed with brine and dried. Removal of solvent gives a yellow solid which is chromatographed over silica gel and eluted 7 8 with petroleum ether to give 0.88 g. (95%) spiro [cycloin which X is halo and all other symbols are as described propane-l,B-(1',1"-tetramethyleneferrocene)] in the form in claim 1. of a yellow solid which is crystallized from ethanol,

Analysis.Calcd. for C H Fe: C, 72.21; H, 6.82; Fe, 20.99. Found: C, 71.89; H, 6.69; Fe, 21.03.

We claim:

1. A compound selected from the class consisting of compounds of the formulae e Fe Formula II. Formula 2 6. The process of preparing a compound of Formula Wherem R 18 hydrogen an alkyl of 1 to 8 carbon atoms 2 of claim 1 which comprises reacting a compound of the an aryl or an aralkyl; X is hydrogen, bromo or chloro, n is 0 to 1; and Y and Z are hydrogen, halo, trifluoroformula methyl or lower alkyl.

2. A compound of claim 1 in which X, Y and Z are h 2 ydrogen.

3. A compound of Formula 2 of claim 1 in which s: R is hydrogen or methyl, X is hydrogen or chloro, and Fe Y and Z are hydrogen.

4. A compound of Formula 1 of claim 1 in which X -(CH is hydrogen or chloro, and Y and Z are hydrogen. Z

5. The method of preparing a compound of Formula 1 of claim 1 which comprises treating a compound of the with an ethyl trihaloacetate to form a compound of the formula formula -(c1r Y CH Fe Fe 6.

H cg 2. 2 2))1 Z 2)n with an ethyl trihaloacetate to form a compound of the in which X is halo and all other symbols are as described formula in claim 1.

References Cited Cottis et al., Chem. and Industry (London) N0. 21,

May 25, 1963, p. 860-1.

TOBIAS E. LEVOW, Primary Examiner. Fe A. P. DEMERS, Assistant Examiner.

(CH9 US. (:1. X.R. 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF COMPOUNDS OF THE FORMULAE 